tbuckley/cabot-search huggingface dataset:
Visualizing meaningful change in small sample sizes.
Authors: Charles Iaconangelo, Daniel Serrano, Shauna McManus
Journal: Journal of Clinical Oncology (2022)

e18656 Background: Patient Reported Outcomes (PROs) are included in trials to incorporate patient voice into the drug development process. In oncology, PROs typically evaluate patient physical function and/or symptom burden. Clinicians need to be able to describe expected patient outcomes in terms of meaningful change in conversations with patients. FDA guidances outline analysis methods for measuring meaningful change, and the results are increasingly used to inform regulatory decisions and in drug packaging. Improving best practices in measuring meaningful change is crucial for regulatory review and to help clinicians communicate effectively with patients. Current best practice under FDA guidance is to compute meaningful within-patient change (MWPC) using an anchor-based approach. The relationship between change scores and anchor groups is visualized via empirical cumulative distribution functions (eCDFs). However, when sample sizes within anchor groups are small, it may be difficult to compute the distribution function. In contrast, a scatterplot approach does not require any computation. The objective was to evaluate under what study conditions (i.e., sample sizes and magnitude of meaningful change) would it be advantageous to interpret meaningful change with a scatterplot approach. Methods: Data simulated to emulate real PRO data from a trial, including attrition due to death, were used to highlight shortcomings in current practice and propose a robust alternative. A simulation study permitted a variety sample sizes and magnitudes of meaningful change to be evaluated. The eCDF was implemented in accordance with current guidance and compared to scatterplots. The scatterplot approach was operationalized as follows: the subject scores were plotted with the baseline scores on the x-axis and the follow-up scores on the y-axis. The scatterplot was stratified by color to represent anchor group-specific scores. Subjects who did not respond at follow-up due to progression or death were plotted in a separate color, using the baseline response and an assigned follow-up score reflecting maximum severity. A 45-degree line represented No Change. The vertical distance between the subject score and the 45-degree line represented the observed change. Results: When sample size was below n = 10 subjects per anchor group, the eCDF yielded uninterpretable visualizations. At sample sizes n = 1-20 per anchor group, the scatterplot approach consistently yielded interpretable visualizations of meaningful change. Conclusions: The scatterplot approach avoids methodological complications and thus ensures transparency in the evaluation of meaningful change. Recommendations to supplement current best practice with the scatterplot approach described above should be considered.
A phase 1/2 study of REGN5093-M114, a METxMET antibody-drug conjugate, in patients with mesenchymal epithelial transition factor (MET)-overexpressing NSCLC.
Authors: Alexander E. Drilon, Mark M. Awad, Shirish M. Gadgeel, Liza C Villaruz, Joshua K. Sabari, Javier Perez, Christopher Daly, Shraddha Patel, Siyu Li, Frank A. Seebach, Israel Lowy, Heather D. Magnan, Petra Rietschel
Journal: Journal of Clinical Oncology (2022)

TPS8593 Background: MET, also called hepatocyte growth factor receptor (HGFR), is a high-affinity transmembrane protein receptor for HGF. MET is overexpressed in various malignancies, including non-small cell lung cancer (NSCLC). MET overexpression can accompany MET exon 14 alteration or de novo/acquired MET amplification. REGN5093-M114 is an antibody drug conjugate composed of a novel linker-payload (M114, carrying the maytansine derivative M24, a potent inhibitor of microtubule assembly) covalently bound to lysine residues on a MET-targeting human IgG4p bispecific antibody, REGN5093. In preclinical models of MET overexpressing cancers, REGN5093-M114 demonstrated significant dose-dependent antitumor activity. Methods: This is an open label, phase 1/2, first-in-human, multicenter dose-escalation study with cohort expansion evaluating REGN5093-M114 in patients with MET-overexpressing NSCLC (NCT04982224). Patients must have advanced stage NSCLC for which there are no approved therapies available expected to confer clinical benefit, with tumor overexpressing MET (≥75% tumor cell staining at 2+) as centrally confirmed by immunohistochemistry. For the expansion phase, patients must have at least one lesion that is measurable by RECIST 1.1. REGN5093-M114 will be administered intravenously once every 3 weeks over 30 minutes until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal. The primary objectives in dose escalation are to evaluate safety, tolerability, PK, and maximum tolerated dose and/or recommended phase 2 dosing regimen of REGN5093-M114. PKs will include the assessment of REGN5093-M114, total antibody, and payload M24 concentrations. The primary objective in dose expansion is to assess preliminary anti-tumor activity of REGN5093-M114 in MET-overexpressing NSCLC as measured by the objective response rate. The secondary objectives of both phases of the study include an evaluation of treatment durability, and the immunogenicity of REGN5093-M114. This study is currently open to enrollment. Clinical trial information: NCT04982224.
EPEN-27. Epigenetic dissection of spinal ependymomas (SP-EPN) separates tumors with and without<i>NF2</i> mutation
Authors: Sina Neyazi, Erika Yamazawa, Catena Kresbach, Genta Nagae, Alicia Eckhardt, Takayoshi Umeda, Lara Pohl, Kenji Tatsuno, Ceren Saygi, Taijun Hana, Malik Alawi, Phyo Kim, Mario M Dorostkar, Fumi Higuchi, Abigail K Suwala, Toshihiro Takami, Annika Wefers, Yuta Nakanishi, Leonille Schweizer, Keisuke Takai, Lara Engertsberger, Takashi Komori, Theresa Mohme, Hirokazu Takami, Martin Mynarek, Masashi Nomura, Karin Lamszus, Akitake Mukasa, Lan Kluwe, Shunsaku Takayanagi, Andreas von Deimling, Kazuhiko Ishii, Martin Benesch, Hideaki Imai, Matija Snuderl, Stephan Frank, Koichi Ichimura, Christian Hagel, Viktor F Mautner, Stefan Rutkowski, Shota Tanaka, Hiroyuki Aburatani, Saito Nobuhito, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract Ependymomas encompass multiple, clinically relevant tumor types based on localization, genetic alterations, and epigenetic and transcriptomic profiles. Tumors belonging to the methylation class of spinal ependymoma (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, molecular data of SP-EPN are scarce, and clear treatment recommendations are lacking. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations. Yet, it remains unclear whether SP-EPN with germline or sporadic NF2 mutations or with NF2 wild type status differ clinically or molecularly. To provide a comprehensive molecular profile of SP-EPN, we integrated epigenetic, genomic, transcriptomic, and histological analyses of up to 237 cases. Clustering of methylation data revealed two distinct molecular SP-EPN subtypes. The distribution of NF2 mutated cases differed significantly across these subtypes (p &amp;lt;0.0001): The vast majority of tumors harboring either a previously known NF2 germline mutation or a sporadic mutation were assigned to subtypes A, whereas subtype B tumors mainly contained NF2 wild type sequences. In addition, subtype A tumors showed a lower frequency of MGMT promoter methylation (p= 0.018) and contained almost all pediatric patients of the cohort. Whole-exome sequencing (30 cases) identified numerous mutations in NF2 wild type and mutated tumors. Mutated genes in NF2 wild type tumors were enriched for genes associated with cell cycle and cytoskeleton. RNA sequencing revealed two distinct transcriptional groups with upregulation of proliferative genes in one group and upregulation of cilial genes in the other group. The molecular subtypes displayed subtle, but significant differences in the appearance of histopathological characteristics, such as surfaces, inflammation, and hyalinized vessels. Investigation of clinical parameters is ongoing and will complete the picture of SP-EPN heterogeneity as an important basis for future clinical decision-making.
What are the patient’s understanding about fecal and urinary incontinence management?
Authors: L. López-Fando Lavalle, I. Senra Bravo, M.D. Sánchez Gallego, V. Viegas, M. Costal, C. Gómez Del Cañizo, I. Galindo, T. Jérez Izquierdo, L. Polanco, D. Carracedo Calvo
Journal: European Urology (2022)
Spatio-temporal delivery of both intra- and extracellular toll-like receptor agonists for enhancing antigen-specific immune responses
Authors: Nannan Wang, Yueyue Zuo, Shengjie Wu, Chenlu Huang, Linhua Zhang, Dunwan Zhu
Journal: Acta Pharmaceutica Sinica B (2022)

For cancer immunotherapy, triggering toll-like receptors (TLRs) in dendritic cells (DCs) can potentiate antigen-based immune responses. Nevertheless, to generate robust and long-lived immune responses, a well-designed nanovaccine should consider different locations of TLRs on DCs and co-deliver both antigens and TLR agonist combinations to synergistically induce optimal antitumor immunity. Herein, we fabricated lipid-polymer hybrid nanoparticles (LPNPs) to spatio-temporally deliver model antigen ovalbumin (OVA) on the surface of the lipid layer, TLR4 agonist monophosphoryl lipid A (MPLA) within the lipid layer, and TLR7 agonist imiquimod (IMQ) in the polymer core to synergistically activate DCs by both extra- and intra-cellular TLRs for enhancing adaptive immune responses. LPNPs-based nanovaccines exhibited a narrow size distribution at the mean diameter of 133.23 nm and zeta potential of -2.36 mV, showed a high OVA loading (around 70.83 μg/mg) and IMQ encapsulation efficiency (88.04%). Our data revealed that LPNPs-based nanovaccines showed great biocompatibility to immune cells and an excellent ability to enhance antigen internalization, thereby promoting DCs maturation and cytokines production. Compared to Free OVA, OVA-LPNPs promoted antigen uptake, lysosome escape, depot effect and migration to secondary lymphatic organs.
Acupuncture for hot flashes in hormone receptor-positive breast cancer, a pooled analysis of individual patient data from parallel randomized trials.
Authors: Weidong Lu, Anita Giobbie-Hurder, Anna Tanasijevic, Sylvia Baedorf Kassis, Sung Hwan Park, Young Ju Jeong, Im Hee Shin, Chang Yao, Hyun Jung Jung, Zhiyuan Zhu, Chao Bao, EunMee Yang, Barbara E Bierer, Jennifer A. Ligibel
Journal: Journal of Clinical Oncology (2022)

12124 Background: Hot flashes are a common side effect of endocrine therapy in breast cancer patients (pts). In a coordinated multinational study, we evaluated the impact of acupuncture on hot flashes and related symptoms in hormone receptor-positive breast cancer pts undergoing adjuvant endocrine therapy in the USA, China, and South Korea. Methods: Parallel randomized trials were conducted at three sites: Dana-Farber Cancer Institute, USA; Jiangsu Hospital of Traditional Chinese Medicine, China; and Daegu Catholic University Medical Center, Republic of Korea, using the same inclusion/exclusion criteria, randomization, and measures. Breast cancer pts receiving adjuvant endocrine therapy and having ≥14 hot flashes per week were randomized equally to acupuncture (A) or usual care (UC); randomization was stratified by number of hot flashes per day (2-6 or 7+). Pts in arm A received a standardized acupuncture protocol twice per week for 10 weeks; pts in the UC arm received usual care. Symptoms were assessed at baseline and week 10. The primary endpoint was change in the Endocrine Symptom Subscale (ESS) of the Functional Assessment of Cancer Therapy-Endocrine Systems (FACT-ES). Secondary endpoints included changes in the FACT-Breast (FACT-B) and Daily Hot Flash Score (DHFS), a measure incorporating hot flash frequency and severity. Target enrollment was 160 pts (USA 80, China 40, Korea 40) providing 84% power to detect a clinically meaningful change in the ESS. Analyses were intention-to-treat. A pooled analysis of individual patient data was performed using linear models adjusted for site and baseline number of hot flashes. Results: Between Jan. 2019 and June 2021, 158 female pts with stage 0-III breast cancer were randomized from the USA (n=78), China (n=40), and South Korea (n=40). Median age was 48 years (range: 25 to 73). At baseline, pts reported similar numbers of hot flashes between study arms (6.2± 4.3 vs. 6.5± 3.8 per day). At week 10, pts in arm A reported statistically significant improvements in ESS score, FACT-B total score and DHFS compared with the UC arm (Table). The reduction in the DHFS from baseline in arm A was 53%. There were no serious adverse events. Conclusions: Acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer-specific quality of life in women undergoing adjuvant hormonal therapy for breast cancer in the USA, China and South Korea. Clinical trial information: NCT00797732, ChiCTR2100045888, KCT0003618. [Table: see text]
Association of Daratumumab Use With Ocular Events in a Case Series of US Adults
Authors: Michelle Nadeau Nguyen, Wiley Chambers, Graça M. Dores, Afrouz Nayernama, S. Christopher Jones
Journal: JAMA Oncology (2022)

This case series uses postmarketing data to evaluate the association of daratumumab use with ocular events such as acute angle-closure glaucoma, myopic shift, and choroidal effusions among US adults.
MEDB-66. Investigating intra-tumoral heterogeneity of extrachromosomal DNA in SHH medulloblastoma
Authors: Owen Chapman, Sunita Sridhar, Robert J Wechsler-Reya, Lukas Chavez, Jill P Mesirov
Journal: Neuro-Oncology (2022)

Abstract Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers, including medulloblastoma (MB), the most common malignant pediatric brain tumor. Our study’s aim is to better understand how ecDNA containing cells can potentiate malignant growth. EcDNA’s role in the development of treatment resistance and association with poor outcomes is hypothesized to arise from its contribution to intra-tumoral heterogeneity and its potential to promote oncogene dependency switching. To analyze the intra-tumoral distribution of ecDNA, we have now simultaneously analyzed the accessible chromatin and gene expression in single cells of a SHH medulloblastoma (MB) patient using multiome single-cell ATAC-seq and gene expression (10X Genomics). Whole genome sequencing (WGS) of this tumor previously revealed a heterozygous somatic TP53 mutation and two distinct ecDNAs: a 3.2Mbp amplicon comprising 3 regions of chr1 and another 4.5Mbp amplicon comprising 23 segments originating from chr7 and chr17. We then used multimodal analysis to describe the tumor cell types, gene expression, variant signatures and estimate ecDNA copy number in the medulloblastoma tumor sample. We identified 12 distinct clusters in the human tumor, 5 of which were determined to be normal non-tumor [OSC1] cells, as identified by specific cell type markers, and 7 of which were determined to be tumor cells. Enrichment of ecDNA was restricted to only one of these tumor clusters. In addition, we also performed the same multiome single-cell analyses in an orthotopic xenograft mouse model derived from this SHH MB patient tumor. In the PDX, 17 clusters were identified, all of which were determined to be tumor cells and enriched for ecDNA. Our preliminary results indicate that tumor cells with ecDNA in the human tumor (particularly the ecDNA enriched cluster) almost exclusively account for [OSC2] the cells in the corresponding PDX, emphasizing the aggressiveness of ecDNA containing cells.
MEDB-48. Infant medulloblastoma - SHH subtype – with residual disease. To treat or not to treat
Authors: Christine Dahl, Sarita Depani, Kriti Hedges, Fernando Aguirregomezcorta, Kristian Aquilina, Owase Jeelani, Olivia Carney, Sniya Sudhakar, Ulrike Loebel, Felice d′Árco, Kshitij Mankad, Darren Hargrave, Mette Jorgensen
Journal: Neuro-Oncology (2022)

Abstract Management of infant medulloblastoma remains a challenge. Front-line chemotherapy can successfully avoid radiation in low-risk infant medulloblastoma. Patients that do relapse can be salvaged long-term with radiotherapy. We report 4 cases of infants with medulloblastoma treated with chemotherapy (HIT2000 protocol) with residual or progressive disease. RESULTS: Four cases of infant medulloblastoma, all MBEN/nodular desmoplastic SHH type B, p53 WT, no MYC / MYCN amplification. CASE 1: 16 month old girl, metastatic lesions in the cerebellum and meningeal enhancement. Germline SUFU mutation. After 3 cycles of chemotherapy MRI showed more enhancement of the residual disease. To inform management, second look surgery was performed. Pathology showed fibrous tissue only, no malignant cells. The child continues to be treated as per HIT2000. CASE 2: 5 month old girl, metastatic lesions in the cerebellum. Germline SUFU mutation. 2 months after end of treatment, MRI demonstrated progression of cerebellar lesion. Surgical resection was performed, pathology showed differentiated mature neuronal tissue. No further treatment; remains in remission 1 year after suspected progression. CASE 3: 27 month old boy, metastatic lesions in cerebellum. Germline SUFU mutation. 1 month post-completion of treatment progressive prominent nodules along the cerebellum and cerebellar leptomeningeal enhancement. Biopsy not feasible so close MRI surveillance was initiated. MRI remains stable 1 year after suspected progression. CASE 4: 30 months old boy, non-metastatic disease. Complete resection. No germline mutation. End-of-treatment MRI showed subtle new intraspinal leptomeningeal deposits and a suspicious left optic tract nodule, subsequent MRI 8 weeks later showed clear progressive disease. Unfortunately, the child died before radiotherapy could be delivered. CONCLUSION: Salvage radiotherapy for infants with medulloblastoma who progress following chemotherapy treatment can be life-saving but risk significant cognitive impairment. Differentiation of medulloblastoma following radio/chemotherapy has been reported. We recommend considering tissue confirmation prior to embarking on further treatment for suspected relapse.
Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors
Authors: Hongru Zhang, Pengfei Yu, Vivek S. Tomar, Xiangjie Chen, Matthew J. Atherton, Zhen Lu, Hong-Guang Zhang, Shifeng Li, Angelica Ortiz, Jun Gui, N. Adrian Leu, Fangxue Yan, Andres Blanco, Mirella L. Meyer-Ficca, Ralph G. Meyer, Daniel P. Beiting, Jinyang Li, Selene Nunez-Cruz, Roddy S. O’Connor, Lexus R. Johnson, Andy J. Minn, Subin S. George, Constantinos Koumenis, J. Alan Diehl, Michael C. Milone, Hui Zheng, Serge Y. Fuchs
Journal: Nature Cancer (2022)
Development of hand-food skin reaction correlates with prognosis of patients with HCC who were treated with sorafenib.
Authors: Young-Sun Lee, Yoonseok Lee, Sang Cheul Oh, Ji Hoon Kim
Journal: Journal of Clinical Oncology (2022)

e16171 Background: Sorafenib is one of the effective systemic therapy in patient with advanced hepatocellular carcinoma (HCC). However, there are few prospective studies that have examined prognostic factors of sorafenib response. In this study, we analyzed prognostic factors of HCC patients who were treated with sorafenib. Methods: Between May 2016 and May 2018, 288 advanced HCC patients treated with sorafenib were enrolled at 13 hospitals. We analyzed possible prognostic factors of sorafenib response (overall survival and progression free survival) using Univariate and Multivariate analyses with Cox proportional hazards regression model. Results: Among the 288 patients, chronic hepatitis B (68.4%) was main cause in development of HCC. 85.4% of patients were in the advanced stage of Barcelona Clinic Liver Cancer. Hand-foot skin reactions (HFSR) were observed in 142 patients (49.2%). The univariate analysis identified presence of ascites, serum albumin level and creatinine level, presence of HFSR as potential prognostic factors for overall survival (OS). In multivariate analysis for OS, presence of HFSR (HR 0.144; 95% CI: 0.063-0.330, p 0.002), albumin level (HR ratio 0.283; 95% CI: 0.148-0.544, p &lt; 0.001), creatinine level (HR 1.395; 95% CI 1.133-1.717, p 0.002) were significant factors of OS. In univariate and multivariate analysis, presence of HFSR (HR 0.212; 95% CI: 0.091-0.495, p &lt; 0.001), and serum albumin level (HR 0.30, 95% CI: 0.158-0.568, p &lt; 0.001) were show significant correlation with progression free survival. Conclusions: Developing HFSR from sorafenib therapy and high serum albumin level were associated with improved OS and PFS. Developing HFSR have been suggested as possible predictor of good sorafenib response. Clinical trial information: NCT03212625.
Impaired seroconversion after SARS-COV-2 mRNA vaccine in patients with thymic epithelial tumors.
Authors: Erica Pietroluongo, Pietro De Placido, Rocco Morra, Margaret Ottaviano, Marianna Tortora, Mariarosaria Saponaro, Luca Pisapia, Giancarlo Del Gaudio, Vitantonio Del Deo, Anna Maria Malfitano, Gustavo Cernera, Carmine De Angelis, Grazia Arpino, Daniela Terracciano, Giuseppe Castaldo, Pietro Formisano, Giovannella Palmieri, Sabino De Placido, Mario Giuliano
Journal: Journal of Clinical Oncology (2022)

8588 Background: Thymic epithelial tumors (TET) are rare malignancies associated with dysregulation of the immune system and humoral and cell mediated immunity abnormalities. Anti-syndrome coronavirus type 2 (SARS-CoV-2) vaccine is effective at preventing COVID-19 morbidity and mortality. No published data are available regarding the immunization in TET patients (pts). The aim of this study was to evaluate the immunization in TET pts who received two doses of mRNA vaccine, by longitudinal serological detection of SARS-COV-2 spike-binding IgG antibody. Methods: Starting from April 2021 to October 2021, consecutive TET pts referred to the Rare Tumors Coordinating Center of Campania Region (CRCTR - Naples, Italy) were enrolled. All study subjects received two doses of COVID-19 mRNA vaccine (BNT162b2 by Pfizer-BioNTech). SARS-CoV-2 spike-binding IgG antibody (Ab) serological levels were analyzed by centralized chemiluminescent immunoassay (CLIA) at different time-points, including before 1 st vaccine dose (T0) and 1 month after 2 nd dose (T2). Cut-off for Ab titers positivity was &gt; 25 AU/mL. Results: Forty pts were enrolled; 23 (57.5%) were female and 17 (42.5%) male. Eleven pts (27.5%) suffered from thymic carcinoma, 28 (70%) thymoma, and 1 (2.5%) thymic hyperplasia. At the time of study enrollment, 20 pts (50%) had no evidence of disease (NED) and were in follow-up; the remaining 20 pts had evidence of disease (ED) by imaging and were receiving systemic treatment (55% oral low-dose etoposide-based therapy, 40% somatostatin analogs + prednisone, 5% supportive care). Immune system disorders were diagnosed in 29 TET pts (72.5%): 19 pts (47.5%) had Good’s Syndrome (GS) and 10 (25%) other immune disorders. At T0, all enrolled pts had negative Ab titers and no prior SARS-CoV-2 infection. At T2, Ab data were available for 37 pts (92.5%): 18 pts (48.7%) had positive Ab titers, whereas 19 (51.3%) did not achieve seroconversion. Among pts with ED, seroconversion was achieved only in 2 cases (11.8%). Lack of seroconversion at T2 was significantly associated with ED (Fisher's exact test p: 0.0001) and with the presence of GS (Fisher's exact test p: 0.0489). No significant association of seroconversion with other immune disorders and disease features was found. Conclusions: Our data showed that TET pts with ED had substantially higher probability of impaired seroconversion after SARS-COV-2 vaccine as compared with NED pts. We warrant further studies to evaluate the role of disease status, anti-tumor treatments and immune disorders in post-vaccine immunization of TET pts.